tbuckley/cabot-search huggingface dataset:
A study of antibody conjugates for the treatment of inflammatory breast cancer.
Authors: Teng Yang, Peng Guo, Qing Wei
Journal: Journal of Clinical Oncology (2023)

e15016 Background: Inflammatory breast cancer (inflammatory carcinoma) is a rare metastatic malignant tumor, it accounts for about 2% of all breast cancer cases. Despite its low incidence, inflammatory breast cancer is highly invasive, its five-year survival rate is less than 41%, making its prognosis the worst of all breast cancer subtypes, and effective drugs are urgently needed in clinical practice. Therefore, our study develops novel antibody conjugate drugs that can target overexpressed-ICAM-1 in inflammatory breast cancer cells as an original molecular target precisely. Methods: In this study, flow cytometry was used to perform precise and quantitative target screening of inflammatory breast cancer cell lines (SUM-149, KPL4), the endocytosis efficiency of ADC drugs was verified by flow cytometry efficiency analysis and single-photon confocal analysis, and the cytotoxicity of different drugs and cell lines was explored by CCK8 experiment. A nude mouse model of orthotopic xenograft inflammatory breast cancer was constructed, and the in vivo therapeutic effect of inflammatory breast cancer was observed by intravenous injection of two ICAM-1 antibody conjugates (ICAM-1-MMAE and ICAM-1-DXD), also the ADC drug structure with the best therapeutic effect for inflammatory breast cancer was screened. Results: ICAM-1 molecule in a variety of inflammatory breast cancer cell lines were highly over-expressed, and the antibody internalization rate was 51% at 4h, and after the peak the endocytosis efficiency slowed down into the plateau stage; ICAM1-MMAE and ICAM1-DXD are safer than first-line chemotherapy agents for breast cancer; The tumor volume was significantly reduced after administration into the orthotopic breast cancer xenograft model, which further verified the obvious effect of ADC drugs in vivo. Conclusions: Both ICAM-1-MMAE and ICAM-1-DXD have shown significant anti-inflammatory breast cancer effects in vitro and in vivo, and this study provides potential antibody conjugate drugs for targeted therapy of inflammatory breast cancer, which is expected to help improve the poor prognosis of inflammatory breast cancer.
Transcriptomic signatures of MSI-high metastatic colorectal cancer to predict efficacy of immune checkpoint inhibitors.
Authors: Claire Gallois, Matteo Landi, Julien Taieb, Sara Lonardi, Francesca Bergamo, Rossana Intini, Giulia Maddalena, Filippo Pietrantonio, Francesca Corti, Margherita Ambrosini, Antonia Martinetti, Marco Maria Germani, Chiara Boccaccio, Guglielmo Vetere, Sophie Mouillet-Richard, Aurélien de Reynies, Pierre Laurent Puig, Chiara Cremolini
Journal: Journal of Clinical Oncology (2023)

3570 Background: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Methods: In a cohort of 103 patients with MSI mCRC treated with ICI, 3’RNAseq was performed from primary tumors resected before the beginning of ICI. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: The unsupervised clustering of this cohort allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromal HIGH -proliferation LOW ”), cluster B (“stromal HIGH -proliferation MED ”), and cluster C (“stromal LOW -proliferation HIGH ”), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p &lt; 0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. Similar results were observed for overall survival (OS).In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.26 95%CI 0.11-0.58, p = 0.001) and cluster C (HR: 0.35 95%CI 0.16-0.78, p = 0.01), compared to patients belonging to cluster A (Table). No association of identified clusters with PFS during non-ICI-based regimens was identified. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromal HIGH -proliferation LOW ” cluster is associated with a lower efficacy of ICI. [Table: see text]
Incidence of infusion related reactions of daratumumab-hyaluronidase-fihj: Pre-post intervention study of premedication omission.
Authors: Kashyap Padmaraju, Kaitlin Kelly, Andrzej J. Jakubowiak, Benjamin Avi Derman
Journal: Journal of Clinical Oncology (2023)

6574 Background: Daratumumab-hyaluronidase-fihj subcutaneous (Dara-SQ) is utilized frequently in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Initially approved as an intravenous formulation, daratumumab (Dara-IV) showed significant infusion related reactions (IRRs), requiring premedication (acetaminophen, diphenhydramine, dexamethasone, and some add montelukast) prior to each dose. Dara-SQ was shown to be noninferior to Dara-IV with significantly fewer IRRs. Despite the reduced IRR risk, indefinite premedication is also recommended in the package insert for Dara-SQ. Given that IRRs are rare after the first dose of Dara-SQ and premedication extends the time for patients in an infusion center, we investigated whether premedication may be safely omitted after the first cycle. Methods: This pre-post interventional quality improvement study included all patients aged 18 years or older diagnosed with MM or amyloidosis that received at least one dose of Dara-SQ between July 1 st , 2020 – December 31 st , 2022. Omission of premedication (excluding dexamethasone) after four doses of Dara-SQ was introduced June 1 st , 2022. The pre-interventional arm followed standard of care with premedication continued (Arm 1) and post-interventional arm included patients with premedication omitted after fourth dose (Arm 2). Patient demographics, prior therapy, Dara-IV exposure, and premedication usage were collected to evaluate the primary endpoint: incidence of IRR after premedication omission. Secondary analysis included any IRR prior to intervention, timing of reaction, reaction management, and post-reaction management. Results: A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included in the study, with a median age of 69 (38-86) years old; 52% African American and 54% male. IRR prior to fourth dose occurred in 1.6% (1/63) for Arm 1 vs. 5.1% (2/39) for Arm 2 [ p= 0.6], Dara-IV exposure was 52.4% (33/63) in Arm 1 vs. 10.2% (4/39) in Arm 2 [ p= 0.02], and indication was newly diagnosed MM in 21% (13/63) of Arm 1 vs. 41% (16/39) of Arm 2 [ p= 0.03]. For the primary objective, there were zero reactions in both arms. All three reactions prior to fourth dose occurred after the first dose of Dara-SQ, with a median time to reaction of 4.8 hours. These were all grade 2 per CTCAE v5.0, with all patients discharged home after reaction, and all patients received subsequent Dara-SQ without issues. For the two reactions prior to fourth dose in Arm 2, premedication was omitted after 6 doses in one patient and 8 doses in the other with no further issues on subsequent doses. Estimated therapy time saved was 194 hours, with an estimated savings of $145,500 thus far. Conclusions: IRRs to Dara-SQ occur early, are rare, and mild in course. Omitting premedication after a minimum of four Dara-SQ doses is safe and carries substantial time savings for patients and infusion centers.
Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.
Authors: Romain Cohen, Morteza Raeisi, Qian Shi, Benoist Chibaudel, Takayuki Yoshino, John Raymond Zalcberg, Richard Adams, Chiara Cremolini, Eric Van Cutsem, Volker Heinemann, Josep Tabernero, Cornelis J. A. Punt, Dirk Arnold, Herbert I. Hurwitz, Jean-Yves Douillard, Alan P. Venook, Leonard B. Saltz, Timothy S. Maughan, Thierry Andre, Aimery De Gramont
Journal: Journal of Clinical Oncology (2023)

3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P &lt; .001) and less SS (31 vs 47%; P &lt; .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]
Prevalence of germline variants in patients with pancreatic neuroendocrine tumors.
Authors: Chirayu Mohindroo, Seyda Baydogan, Parul Agarwal, Dan Laheru, Robin Wright, Laura Prakash, Maureen E Mork, Alison Klein, Jess Maxwell, Matthew H. G. Katz, Arvind Dasari, Michael Paul Kim, Jin He, Florencia McAllister, Ana De Jesus-Acosta
Journal: Journal of Clinical Oncology (2023)

4135 Background: About 10% of pancreatic neuroendocrine tumors (pNETs) are thought to be related to inherited syndromes, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Here, we report the prevalence of pathological/likely pathological germline variants (PV/LPV) in 2 cohorts: 1) High-risk and 2) Unselected. Methods: We retrospectively collected clinical data of patients with biopsy proven pNETs seen at MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH). Cohort 1 (high risk cohort) included 132 patients seen at MDACC, who underwent germline testing based on high-risk criteria such as early onset, personal or family history of cancer and syndromic features between 2013 -2019. Cohort 2 (unselected cohort) included 106 patients seen at JHH, who underwent germline testing following their diagnosis of pNETs between 2020 to 2022. Results: In the high-risk cohort (n = 132), 33% (n = 44) had PV/LPV, and 17 % (n = 22) had a variant of unknown significance (VUS). Amongst the 132 patients, 35% underwent multigene panel testing, 53% had targeted germline testing and 12% had a physician documented outside test diagnosis. The demographics consisted of 52%(n = 69) females, 67% (n = 88) white, 54%(n = 71) had metastatic disease, 58%(n = 76) underwent surgical resection. WHO grading (n = 77) is as follows G1 (39%), G2 (59%), G3 (2%). In the unselected cohort (n = 106), 21% (n = 22) had PV/LPV, 28 % (n = 30) had a VUS. Of these, 93% of the patients underwent multigene panel testing. The demographics consisted of 42% (n = 44) females, 67% (n = 88) white, 48% (n = 51) had metastatic disease, 60% (n = 64) underwent surgical resection, WHO grading (n = 93) is as follows G1 (37%), G2 (49%), G3 (14%). Conclusions: PV/LPV are prevalent in patients with sporadic pNET irrespective of high-risk features or family history. While in the high-risk patients there is a higher prevalence, we also identified a 21% prevalence of PV/LPV with universal germline testing in the unselected cohort. In both cohorts, we identified a high number of mutations in the DNA repair pathway not previously described, which could affect subsequent therapies and surveillance for patients and their family members. The findings support upfront universal germline testing in all patients with diagnosis of pNETs. [Table: see text]
Utility of next generation sequencing (NGS) in advanced malignancies in a community hospital in an underserved area: A game changer?
Authors: Krishna Desai, Sabah Iqbal, Bohdan Baralo, Kristal Pereira, Akhil Jain, Sohiel Deshpande, Mahvish Renzu, Vidhi Mehta, Manzoor Rather, Rajesh Thirumaran
Journal: Journal of Clinical Oncology (2023)

e15037 Background: Next Generation Sequencing (NGS) is a revolutionary test used in advanced malignancies to study specific mutations, define tumor burdens, &amp; design personalized treatment plans based on the target mutations. With this study, our aim is to highlight the role of NGS, especially in a community hospital &amp; emphasize on its implementation as a standard of care in advanced metastatic cancers. Methods: We retrospectively reviewed the charts of 51 patients after IRB approval, aged &gt; 18 years with no specific demographic restrictions, with advanced malignancies who had NGS at Mercy Catholic Medical Center, PA. Results: Of 51 patients, 25 were males &amp; 26 were females, 44 patients had positive results on NGS. 100 types of mutations were identified &amp; 338 mutations in total were found. Lung cancer had highest mutations (41.17%-21/51), followed by colon (25.49% - 13/51), breast, ovarian &amp; endometrium (13.72% 7/51), &amp; the rest comprised of GI malignancies &amp; prostate cancers. Of 100 mutations, 32% (32/100) had actionable targets &amp; received NGS directed chemoimmunotherapy, 22% (22/100) mutations had experimental chemo-immunotherapeutic drugs, &amp; 49% (49/100) had no specific NGS directed therapy actionable/target mutation. The most common (1,2,3) &amp; some rare mutations (4,5 and 6) with directed immunotherapy noted on NGS are listed in Table 1. Conclusions: As per our study, 86.27% of the sample size showed positive results on NGS. 32% of these mutations had NGS directed chemoimmunotherapy against these target mutations. In contrary to standard treatment regimens, a personalized treatment plan was developed for these patients, thereby curbing further progression &amp; improving survival in patients with advanced cancer. For example, a patient with stage IV colon cancer who was progressing on the standard treatment with FOLFOX (Folinic acid, flurouracil and oxaliplatin), was started on Ivosedenib, after undergoing NGS and showed marked improvement clinically and radiologically. 29 out of 43 guidelines for various malignancies established by National Comprehensive Cancer Network highlight the significance of NGS. With this study, our goal is to emphasize on the utility of NGS in patients with advanced cancer &amp; the need for it to be incorporated as the standard of care, in small &amp; mid-tier community hospitals, which would need a devised plan for its implementation. [Table: see text]
Evaluation of the prevalence of MET and protein tyrosine kinase 7 expression in non-small cell lung cancer to evaluate overlap of ADC antigens.
Authors: Peter J. Ansell, D. Ross Camidge, Shobhit Baijal, Xiaoyu Xia, Athanasios Vasilopoulos, Martha Li, Ramya Seshadri, Leonidas Arvanitis, Sidney S. Lindsey, Mona H. Cai, Yookyung Christy Choi, Christine Ratajczak, Edwin E. Jeng, Stephen B. Gruber, Shun Lu
Journal: Journal of Clinical Oncology (2023)

e21105 Background: Biomarker-targeted antibody-drug conjugates (ADCs) have shown promise in treating lung cancer. Telisotuzumab vedotin (Teliso-V; ABBV-399) is a first-in-class MET (also known as c-Met)-directed ADC comprising the monoclonal antibody telisotuzumab (ABT-700) conjugated to a cytotoxic microtubule inhibitor, monomethyl auristatin E (MMAE), via a cleavable dipeptide linker. In the phase 2 LUMINOSITY study (NCT03539536), Teliso-V demonstrated promising anticancer activity in previously treated patients with MET-overexpressing (OE), non-squamous epidermal growth factor receptor wild type ( EGFR WT) non-small cell lung cancer (NSCLC; 52.2% overall response rate in MET OE high group, 36.5% in all MET OE cohort [intermediate and high]) and an acceptable safety profile (Camidge et al. J Clin Oncol. 2022;40:16 suppl, 9016). These data provide proof of concept that biomarker-selected MMAE-based ADCs could be beneficial to patients with NSCLC. Cofetuzumab pelidotin (ABBV-647), an ADC with a similar composition to Teliso-V, contains an anti-protein tyrosine kinase 7 (PTK7) monoclonal antibody (hu6MO24) conjugated to a microtubule-inhibiting cytotoxin, Aur0101 auristatin, via a cleavable cysteine-reactive linker. PTK7 expression and oncogenic functions have been reported in several cancers. We sought to establish the co-prevalence of MET OE and PTK7 in NSCLC to understand if both these antigens targeted by ADCs are co-expressed or present in distinct tumors. Methods: Antigen prevalence was analyzed in tumor samples from patients at the City of Hope National Medical Center with non-squamous NSCLC and EGFR WT or unknown status. Immunohistochemistry (IHC) assays used were MET (SP44) Assay for MET OE (Roche Tissue Diagnostics; positive if ≥25% cells at 3+ intensity) and an AbbVie-developed assay for PTK7 expression (positive if ≥90% cells at ≥2+ intensity). Results: A total of 148 patients (median age 67 years, 52% stage ≥III at diagnosis, 68% ECOG 0–2) were screened (data shown in table). About 24% of the patients were MET IHC positive, whereas 11% were PTK7 IHC positive. Further, MET OE and PTK7 had complementary prevalence with only 3% of the patients co-expressing both antigens. Conclusions: MET OE and PTK7 expression by IHC were found to be complementary in patients with non-squamous EGFR WT/unknown NSCLC. About 32% of patients were positive for MET OE or PTK7 expression or both. Data represent patients from a single center and more pre-treatment tissue samples that were viable and available. These IHC findings suggest that MET OE and PTK7 are indeed complementary NSCLC biomarkers. [Table: see text]
Intrapatient comparative efficacy of selective RET inhibitors using growth modulation index in patients with RET aberrant cancers.
Authors: Mohamed Alaa Gouda, Jibran Ahmed, Blessie Elizabeth Nelson, Mirella Nardo, Jason Roszik, Maria E. Cabanillas, Mimi I-Nan Hu, Naifa Lamki Busaidy, Steven I. Sherman, Ramona Dadu, Aung Naing, Daniel D. Karp, Jordi Rodon Ahnert, David S. Hong, Yasir Y Elamin, George R. Blumenschein, John Heymach, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2023)

3086 Background: Selective RET inhibitors (RETi) have changed the paradigm for treatment of RET altered cancers. Current evidence on their efficacy comes from single-arm basket trials. In this study, we performed intrapatient efficacy comparison between approved selective RETi (selpercatinib and pralsetinib) and prior and/or subsequent therapies. We used growth modulation index (GMI) as a tool to compare efficacy, where a value of &gt;1.33 is presumed a cutoff to establish superior efficacy. Methods: We included patients with RET-positive tumors who were treated at our institution as part of RETi clinical trials. We excluded patients with no other systemic therapy received before or after the RETi of interest. We also excluded patients who received both drugs to avoid overlapping efficacy bias, and patients who were treated for ≤ 30 days or had non-evaluable disease. Since some patients have been treated beyond progression or discontinued RETi due to intolerance, we used ratios for both time to treatment takeoff (TTT) and time to progression (TTP) to compare efficacy of RETi (at the RETi treatment line (n)) to prior therapy (n-1) and to subsequent therapy (n+1). GMI was defined as the ratio between TTT/TTT (n±1) or TTP to TTP (n±1). Results: We included 66 patients who received RETi and met our inclusion criteria [39 received selpercatinib and 27 received pralsetinib]. Most patients had GMI&gt;1.33 using either TTT or TTP (61% (n=40) and 58% (n=38), respectively). The median GMI based on pre-RETi therapy was 2.1 and 1.6 (using TTT and TTP, respectively); while the median GMI based on post-RETi therapy was 4.9 and 4.4 (using TTT and TTP, respectively). Patients with GMI&gt;1.33 were more likely to have PR as best response compared to patients with GMI&lt;1.33 (85% vs 53%, p=0.005 using TTT; and 87% vs 54%, p=0.003 using TTP). GMI using TTT (n/n-1) was higher in patients with RET fusions compared to patients with RET mutations (3.7 vs 1.4, p=0.048). GMI using TTT and GMI using TTP(n/n+1) were lower in patients with WBCs &lt;8 at baseline (2.6 vs 13.8, p=0.014; 2.6 vs 11.1, p=0.014; for TTT and TTP) and GI cancer diagnosis (0.4 vs 9.3, p=0.042; 0.4 vs 10.4, p=0.042; for TTT and TTP). Conclusions: Intrapatient efficacy comparisons are feasible using GMI calculations and provide a proof of concept on the favorability of selective RETi compared to other systemic therapies. [Table: see text]